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Mechanism and Selectivity of Bio-inspired Cinchona Alkaloid Derivatives Catalyzed Asymmetric Olefin Isomerization: A Computational Study Xiao-Song Xue, Xin Li, Ao Yu, Chen Yang, Chan Song, and Jin-Pei Cheng J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja309133z • Publication Date (Web): 03 May 2013 Downloaded from http://pubs.acs.org on May 6, 2013

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Journal of the American Chemical Society

Mechanism and Selectivity of Bio-inspired Cinchona Alkaloid Derivatives Catalyzed Asymmetric Olefin Isomerization: A Computational Study Xiao-Song Xue†, ⊥, Xin Li†, Ao Yu‡,*, Chen Yang†, Chan Song‡, and Jin-Pei Cheng†,* †

State Key Laboratory of Elemento-organic Chemistry, ⊥Computational Center of Molecular Science, and ‡Central Laboratory, College of Chemistry, Nankai University, Tianjin 300071, China

ABSTRACT: Asymmetric olefin isomerization of β,γ- to α,β-unsaturated butenolides catalyzed by novel cinchona alkaloid derivatives was investigated in-depth using density functional theory (M05-2x and B2PLYP-D). Three possible mechanistic scenarios, differing in the binding modes of the substrate to the catalyst, have been evaluated. Computations revealed that both the protonated quinuclidine and the 6'-OH of catalysts may act as the proton donor in the stereo-controlling step. Variation of the catalytic activity and enantioselectivity by tuning the electronic effect of catalyst was well reproduced computationally. It suggested that, for certain acid-base bifunctional chiral catalysts, the acid-base active sites of catalysts may inter-convert and give new catalyst varieties of higher activity and selectivity. In addition, the non-covalent interactions in the stereo-controlling transition state structures were identified and their strength was quantitatively estimated. The weak non-conventional C-H…O hydrogen bonding interactions were found to be crucial to inducing the enantioselectivity of the cinchona alkaloid derivatives catalyzed asymmetric olefin isomerization. The computational results provided further theoretical evidence that the rate limiting step of this bio-inspired organo-catalytic olefin isomerization is inconsistent with that of the enzyme catalyzed olefin isomerization.

1. Introduction The enzyme-mediated olefin isomerization, such as the ∆53-ketosteroid isomerase (KSI) catalyzed isomerization of ∆53-ketosteroids to the conjugated ∆4-3-ketosteroids (Scheme 1A), is a common and important class of chemical reactions in biology.1 Enzymes, as the nature’s catalyst, have been a great source of inspiration for the development of new catalytic processes. By examining the chemical building blocks and the modes of substrate activation in biosynthetic pathways, considerable insights can be obtained and then similar transformations could be developed.2 Subsequently, an explosive growth in the field of asymmetric organo-catalysis with an impressive amount of new catalysts and their applications in various reaction types were witnessed in the last decade.3 Despite great success was achieved in asymmetric organocatalysis, the enantioselective olefin isomerization catalyzed by chiral organic small molecules remains a unusual challenge.4 Most recently, as inspired by nature’s KSI, Deng and coworkers realized a general and highly enantioselective olefin isomerization via biomimetic proton transfer catalysis with a novel cinchona alkaloid derived catalyst QD-1a (Scheme 1B).5 The strategy of “electronic tuning of the catalyst”6 was successfully applied to improve catalytic activity and selectivity. Ingeniously oxidizing the quinoline ring N of 6'-OH cinchona alkaloid (QD-1b) into its N-oxide analogue (QD-1a) achieved a significant enhancement of catalytic activity and selectivity (Scheme 1B). It was reported that the catalyst QD-1a could catalyze a broad range of β,γ-butenolides to yield α,βunsaturated butenolides with excellent yields and enantiose-

lectivities.5 The γ-substituted α,β-unsaturated butenolides are a common structural motif in a broad array of natural products7 and they are versatile chiral building blocks in asymmetric synthesis.8 Therefore, substantial attention has been paid to develop efficient methods for optically active γ-alkyl α,βunsaturated butenolides synthesis.9 Deng’s work not only provided a valuable method for the asymmetric synthesis of chiral α,β-unsaturated butenolides but also demonstrated an excellent example of mimicking enzymatic catalysis with artificial organic small molecule structures, one of the most fascinating and provocative challenges presented by Nature. Some key issues of the bio-inspired asymmetric organocatalytic olefin isomerization remain obscure, however. Firstly, though the cinchona alkaloids were proposed to be the KSI mimic, they have different rate limiting steps. Deng’s preliminary kinetic studies suggested that the protonation step be the rate-limiting step of the organo-catalytic asymmetric olefin isomerization,5 whereas the KSI catalyzed olefin isomerization features a rate-limiting deprotonation.1a Secondly, the preferred binding mode between the substrate and catalyst in the stereo-controlling transition state structure remains elusive. Whether the protonated quinuclidine, or the 6'-OH group of catalyst, acts as the proton donor in the stereo-controlling step, is still an open question. Thirdly, the origin of asymmetric induction in the cinchona alkaloids catalyzed olefin isomerization is not yet known, though it is of great importance for understanding the reaction and for developing new reactions. Finally, although the strategy of “electronic tuning of the catalyst” has been nicely applied to optimize the catalytic activity and selectivity, the underlying reasons is not very clear.

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Scheme 1. Enzyme (KSI) and Organic Small Molecules Catalyzed Olefin Isomerization via Proton Shift Processes

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Quantum mechanical investigations on proline catalyzed asymmetric aldol reactions featured the beginning of theoretical mechanism study of organocatalysis.10 From then on, a great number of important organo-catalytic systems has been successfully investigated with this powerful tool,11 which has demonstrated that accurate quantum chemical calculations can provide valuable insights into the origin of the activity and selectivity of organo-catalytic process.12 Due to commercial availability and facile modification, cinchona alkaloids and their derivatives have been extensively used as catalysts in asymmetric synthesis.13-16 Though the development of cinchona-derived compounds catalyzed reactions has emerged as a frontier of organocatalysis, computational mechanistic studies on these systems have received very limited attention.12b,17 Owing to the high importance of this biomimetic asymmetric proton transfer catalysis, we have conducted, as part of our continuing efforts in mechanism study of asymmetric organocatalysis,18 an in-depth computational investigation of the novel cinchona alkaloid derivatives promoted olefin isomerization of butenolides. In the present study, we first investigated various possible mechanistic scenarios that differ in catalytic modes. Calculation revealed that both the protonated quinuclidine and the 6'OH of catalysts may function as the proton donor in the stereocontrolling step. Differing from previous mechanistic hypothesis,5 it is the 6'-OH in this case that acts as the proton donor in the most favored catalytic mode of catalyst QD-1a. In all three mechanistic possibilities, γ-protonation was predicted to be the rate-limiting step of the QD-1a catalyzed reaction, which provided theoretical evidence that the rate-limiting step of this organo-catalytic olefin isomerization differs from that of the enzyme catalyzed olefin isomerization. Next, we explored the origin of selectivity for this eye-catching transformation. An analysis of the electron density and their reduced density gradient (RDG) isosurface19 of the stereo-controlling transition state structures revealed that the weak non-conventional hydrogen bonds (C-H…O)20,21 play a crucial role in inducing selectivity. Finally, the electronic effect of the catalyst on the catalytic activity and enantioselectivity was analyzed. It was found that tuning the electronic effect of the catalyst altered

the most favored catalytic mode. Contrasted with QD-1a, the most favored catalytic mode for QD-1b uses the protonated quinuclidine as the proton donor in the stereo-controlling step. The present study would add new insight into the current understanding of electronic effect of the catalysts,6a,b and may hold general implication for cinchona alkaloids and other acidbase bifunctional chiral catalysts catalyzed reactions.22 2. Computational methods The recently developed M05-2x functional,23 together with the standard 6-31+G(d) basis set, were used for optimizing the geometry of all the minima and transition states (TS) in solution. Houk and coworkers reported very good agreement between the M05-2x functional predictions and experimental observation for the cinchona alkaloid catalyzed rearrangement of allylic trichloroacetimidate.17c The new SMD solvation model was used to account for the effects of dichloromethane (DCM) environment.24 Dielectric constant of 8.93 was used for DCM. In addition, all the optimized structures were confirmed by frequency calculations to be either minima or transition states using the same level of theory. Single point energy calculations were performed at the M05-2x/6-311+G(2d,p) and B2PLYP-D/6-31+G(d,p) level with the M05-2x/6-31+G(d) (SMD) structures. The B2PLYP-D is double-hybrid density functional with long-range dispersion correction.25 All calculations were carried out with the GAUSSIAN 09 packages.26 All energetics reported throughout the text are in kcal/mol and the bond lengths are in angstroms (Å). Structures were generated using CYLview and VMD.27 3. Results and Discussion The catalyst QD-1a catalyzed isomerization of γ-methyl β,γbutenolide (R1) to γ-methyl α,β-butenolide (P1) (Scheme 2) was firstly used as the model reaction to explore the details of the reaction mechanism and the origin of enantioselectivity. Then, the catalyst QD-1b catalyzed same isomerization reaction was used to investigate the electronic effect of the catalyst on the catalytic mode, activity, and enantioselectivity.


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Figure 1. Energies and optimized geometries in Scenario I for the QD-1a catalyzed isomerization calculated with M05-2x/631+G(d)(SMD).

Scheme 2. Isomerization of γ-Methyl β,γ-Butenolide (R1) to γ-Methyl α,β-Butenolide (P1) Catalyzed by the Novel Cinchona Alkaloid Derivative QD-1a

On the basis of the previous experimental and computational studies of the cinchona alkaloids catalyzed reactions,14d,17 the conformation space of catalyst QD-1a and transition states were studied. The lowest energy anti-open conformation of catalyst was considered in the present study.28 Mechanism of QD-1a Catalyzed Reaction The proposed catalytic mechanism for the QD-1a catalyzed olefin isomerization of butenolides consists of two processes, the deprotonation of α-carbon of substrate R1 and the subsequent protonation of γ-carbon in the same substrate molecule.5 Considering different binding modes between the substrate and catalyst, at least three possible mechanistic scenarios can be envisioned. In Scenario I, the substrate R1 binds to catalyst QD-1a by hydrogen bonding interaction between the carbonyl oxygen of R1 and the 6'-OH of QD-1a, and the αdeprotonation and γ-protonation are achieved with the quinu-

clidine nitrogen and the protonated quinuclidine, respectively. In Scenario II, the substrate R1 binds to catalyst QD-1a by hydrogen bonding interaction between the carbonyl oxygen of R1 and the 9-OH of QD-1a. The deprotonation and protonation are similarly achieved as in Scenario I. In Scenario III, the substrate R1 binds to the protonated quinuclidine of QD1a by hydrogen bonding interaction. The γ-protonation is achieved with the 6'-OH of catalyst QD-1a. The M05-2x/631+G(d)(SMD) calculated results of these mechanistic scenarios that lead to the experimentally observed major s-product were given in Figure 1-3 (for the r-product, see Figure S9-S11 in Supporting Information). Scenario I of QD-1a catalyzed reaction. The first step in the mechanistic Scenario I of QD-1a catalyzed reaction is the coordination of the substrate R1 with catalyst QD-1a by forming the hydrogen bond between the carbonyl oxygen (O1'') of R1 and the 6'-OH of QD-1a (Figure 1). This complexation process, generating CP1a, is endergonic by 1.3 kcal/mol due to the entropy penalty for bringing two molecules together.29 The distance of the hydrogen bond between H10' and O1'' is 1.851 Å in CP1a. Deprotonation of the α-proton (H7'') of R1 proceeds via TS1a, leading to intermediate CP2a with a barrier of 14.4 kcal/mol in free energy. During the deprotonation process, negative charge is gradually developed on the O1'' atom of R1. As a result, the interaction between the 6'-OH of QD-1a and the carbonyl oxygen of R1 is strengthened, as demonstrated by the H10'…O1'' distance shortening from 1.851 Å in CP1a to 1.768 Å in TS1a and 1.614 Å in CP2a. The CP2a is 6.5 kcal/mol downhill from TS1a.



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Figure 2. Energies and optimized geometries in Scenario II for the QD-1a catalyzed isomerization calculated with M05-2x/631+G(d)(SMD).

Protonation of the γ-carbon (C4'') by the protonated quinuclidine occurs via TS2a(s) with a barrier of 10.6 kcal/mol in free energy. In contrast to the deprotonation process, the hydrogen bonding interaction between the O1'' and the 6'-OH is weakened during protonation due to the gradually decreased negative charges on the O1'' atom. The H10'…O1'' distance is lengthened from 1.614 Å in CP2a to 1.707 Å in TS2a(s) and 1.800 Å in CP3a. The dissociation of CP3a leads to the release of the product. Reviewing the Scenario I of the QD-1a catalyzed reaction, the γ-protonation is the rate-limiting step, which requires an overall activation free energy of 19.8 kcal/mol in DCM. Scenario II of QD-1a catalyzed reaction. Previous experiments and calculations also showed that the 9-OH group of cinchona alkaloids played an important role in some asymmetric catalytic reactions by hydrogen bonding with substrates.13b,17c,d,30 Thus, it is reasonable to investigate the catalytic activity of 9-OH in QD-1a. In Scenario II, the substrate R1 binds to the catalyst via a hydrogen bonding interaction between the carbonyl oxygen (O1'') of R1 and the 9-OH group of QD-1a (Figure 2). CP1c is energetically 4.9 kcal/mol less stable than CP1a. The hydrogen bond distance between H11 and O1'' is 1.868 Å in CP1c, which is 0.017 Å longer than that in CP1a. This is consistent with the fact that the 9-OH group is a weaker proton donor than 6'-OH due to its lower acidity. The subsequent α-deprotonation proceeds via TS1c with a barrier of 11.9 kcal/mol. Similarly, the hydrogen bonding interaction between O1'' and H11 is strengthened as the H7'' of R1 is transferring to the N1 of QD-1a. The calculation showed that γ-protonation is the rate-limiting step in Scenario II, requiring an overall activation free energy of 26.1 kcal/mol, which is 6.3 kcal/mol higher than that in Scenario I. It is consistent with the experimental observation that the activity of the 9-OH cincho-

na alkaloid catalyzed olefin isomerization is significantly lower than that of the 6'-OH cinchona alkaloid.5 Scheme 3. Free Energies Required for the Dissociation and γ-Protonation of CP2a Calculated with M05-2x/631+G(d)(SMD) -

O

O Ionic hydrogen bonding

O H O R1+QD-1a 0.0 O

NH...π hydroge n bonding

O

H H H N H OH

N

∆G (kcal/mol)

+

CP2a 9.2

CH3

ss Di

tio ic a oc

CH 3

H H N+ H OH +

n

O

γ -P

OH

N 24.9

ro ton at i TS2a(s) on 19.8

P1(s)+QD-1a -1.0

Scenario III of QD-1a catalyzed reaction. Deng and coworker proposed that the 6'-OH of QD-1a might also act as proton donor in the stereo-controlling step.5 Our calculation showed, however, that the sum of free energies of the separated butenolide anion and protonated QD-1a is 24.9 kcal/mol higher than that of R1 and QD-1a (Scheme 3).31 Because the γ-protonation via TS2a(s) needs only 19.8 kcal/mol to pass through, it should be not favorable for intermediate CP2a to dissociate into the protonated QD-1a and butenolide ion, and then finish the γ-protonation with 6'-OH as the proton donor. This suggests that there should be other complexed form besides CP2a to bind the catalyst and substrate together. These dissociation and protonation steps were further validated by the additional high level M05-2x/6-311+G(2d,p)//M05-2x/631+G(d)(SMD) and B2PLYP-D/6-31+G(d,p)//M05-2x/631+G(d)(SMD) calculations (see Scheme S1 in Supporting Information). Two possible reasons might account for the high


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energy barrier required for dissociation of intermediate CP2a into the protonated QD-1a and butenolide ion. One is due to the high instability of butenolide ion in less polar DCM, and the other should be related to that the dissociation requests breaking a +N-H…π hydrogen bond and an ionic hydrogen bond (O-H…O-), whose strength has been shown to be 5 to 35 kcal/mol, up to a third of the strength of covalent bonds.32 On the other hand, it was reported that a very small amount of the zwitterionic form (6HQ') of 6-hydroxyquinoline (6HQ) could coexist with the parent 6HQ (Scheme 4) under neutral conditions based on a meticulous analysis of their absorption spectra.33 Moreover, it was also shown that oxidization of 6HQ into its N-oxide form (6HQNO) significantly enhanced its acidity and thus increased the propensity of donating the proton of the 6-hydroxy group.34 Based on these observations, it can be expected that the zwitterion ion QD-1a' may also coexist with its neutral N-oxide form QD-1a. The present calculation has verified the hypothesis that QD-1a is easier to inter-covert into its zwitterion ion QD-1a' than QD-1b, although the amount of QD-1a' might be low (cf. the difference of relative free energies between QD-1a/QD-1a' and QD1b/QD-1b' in Scheme 4). Scheme 4. Possible Tautomeric Form of 6HQ, 6HQNO, QD-1a and QD-1b.35

absorbance spectra. And lucky enough, the coexistence of the zwitterion ion QD-1a' was indeed experimentally observed by UV-Vis in the present work. Under neutral conditions, a strong absorbance with maxima at 327 nm, which is assigned to neutral QD-1a, is clearly observed (Figure 3, in green). A closer inspection further shows that there is also a notable weak absorbance from 370 to 440 nm (with the main peak at 395 nm), which was suspected to reflect the existence of the zwitterion ion QD-1a' in low concentration. This was later confirmed by varying the pH of the solution. Addition of an acid solution (HCl) into this system caused a total disappearance of the absorbance from 370 to 440 nm (Figure 3, in blue), while adding a basic solution (NaOH) resulted in a gradual increase of the band at 395 nm (Figure 3, in pink). These experimental results are clearly in line with the hypothesis from calculation.

Abs / A.U.

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2.6 Under basic conditions 2.4 2.2 Under neutral condition 2.0 Under acidic conditions 1.8 1.6 1.4 1.2 1.0 Without adding acid/base 0.8 0.6 0.4 0.2 From acidic to baisc conditions 0.0 280 300 320 340 360 380 400 420 440 460 480 500

λ (nm)

Figure 3. Variations of absorption spectra of QD-1a in methanol as added acid or base.

In order to find some unambiguous support from experiment for the species suggested by calculation, we have deliberately synthesized QD-1a and conducted the research using NMR and UV-Vis (for details, see Part K-M in Supporting Information). It is known that the characteristic absorbance band of anionic 6HQNO' of the N-oxide 6-hydroxyquinoline in methanol consisted of a peak at 385nm, while that of the neutral 6HQNO is 323 nm.34 Due to that QD-1a/QD-1a' have very similar structural unit as in 6HQNO/6HQNO', QD-1a and QD-1a' could be expected to be differentiable by their

On the basis of the above, the third catalytic cycle in Scenario III could be envisaged. The QD-1a first converts to the zwitterion ion QD-1a', in which the 6'-O- unit functions as a base to deprotonate the α-proton of R1 while the protonated quinulcidine works as the hydrogen bond donor to interact with the carbonyl oxygen of R1. Figure 4 shows the calculated results. The binding of R1 to QD-1a' is realized by hydrogen bonding interaction between the protonated quinulcidine (N1-H10') and the carbonyl oxygen (O1''), and forms CP1e, which is 8.2 kcal/mol above the separated reactant and catalyst. The hydrogen bond distances, N1-H10'…O1'' and C6'-O9'…H7'' in CP1e, are 1.888 Å and 2.134 Å, respectively. Deprotonation of the α-proton (H7'') of R1 by the 6'-O- unit of QD-1a' proceeds via TS1e, and has a barrier of 8.1kcal/mol in free energy. The γ-protonation with 6'-OH as the proton donor proceeds via TS2e(s) and is the rate-limiting step in Scenario III, requiring an overall activation free energy of 18.1 kcal/mol.36 Reviewing the three mechanistic scenarios aforementioned, the γ-protonation was predicted to be the rate-limiting step in all these mechanistic pathways (Figure 5). This is in line with Deng’s kinetic studies.5 The overall activation free energy in Scenario III was predicted to be 1.7 kcal/mol and 8.0 kcal/mol lower than that in Scenario I and Scenario II, respectively.



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Figure 4. Energies and optimized geometries in Scenario III for the QD-1a catalyzed isomerization calculated with M05-2x/631+G(d)(SMD).

Figure 5. Potential energy surface of QD-1a catalyzed isomerization calculated with M05-2x/6-31+G(d)(SMD).

Thus, Scenario III should be the most favored mechanism for the QD-1a catalyzed isomerization of γ-methyl β,γ-butenolide to γ-methyl α,β-butenolide. Since Scenario III is only 1.7 kcal/mol favored over Scenario I, these two mechanisms could compete with one another. The more precise calculations using the M05-2x/6-311+G(2d,p)//M05-2x/6-31+G(d)(SMD) and B2PLYP-D/6-31+G(d,p)//M05-2x/6-31+G(d)(SMD) methods gave similar relative energies (see Figure S15 in Supporting Information). The overall reaction was calculated to be exergonic by -1.0 kcal/mol. The formation of more stable conjugated α,βunsaturated butenolides would be the driving force for these

olefin isomerizations. Moreover, the calculation predicted that the isomerization of α,γ-dimethyl β,γ-butenolide (R2) to α,γdimethyl α,β-butenolide (P2) are exergonic by -4.9 kcal/mol (Scheme S2 in Supporting Information), explaining the intriguing experimental observation that the γ-methyl α,βbutenolide (P1) underwent easy racemization and that no detectable racemization was observed for the α,γ-disubstituted β,γ-unsaturated butenolides even at room temperature. Origin of Selectivity of QD-1a Catalyzed Reaction Since the γ-protonation is the rate-limiting and stereocontrolling step of the QD-1a catalyzed isomerization of R1 to P1 and the overall activation free barrier in Scenario II is at


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least 6 kcal/mol higher than that in Scenarios I or III, we focused our attention on the transition state structures TS2a(s), TS2b(r), TS2e(s), and TS2f(r) in discussing the origin of selectivity. According to the relative free energies (Figure 6), the major s-product observed in the QD-1a catalyzed isomerization should mainly arise from TS2e(s) while the minor rproduct from TS2f(r). On the basis of the traditional transition state theory, the ee value of the QD-1a catalyzed isomerization of R1 to P1 can be evaluated by eq. 1, where R is the ideal gas constant, T = 253.15. The predicated ee was 98 %, which is very close to the experimental value 92%. Interestingly, the calculation using a model catalyst, in which the 9-OH was replaced by a hydrogen atom, gives 92% ee for the same isomerization (Figure S17 in Supporting Information). It suggests that 9-OH and the chirality at C9 have a minor effect on the selectivity.

the QD-1a catalyzed isomerization of R1 to P1 was conducted by using the NCIPLOT19 and Multiwfn.38 The results are presented in Figure 6. It is clear that several stabilizing CH…O20,21 and C-H…π interactions39 are present in these transition state structures. However, it is still not easy to discern which hydrogen bond is the major factor in governing selectivity. Therefore, quantitative description of the strength of the hydrogen bonds involved in the hydrogen bond network in transition state structures would be highly desirable, because it can be directly used to quantitatively interpret the origin of selectivity. In recent years, there are numerous studies using Quantum Theory of Atoms in Molecules (QTAIM) to investigate the interatomic interactions in terms of the topological properties of electron density.40 The analysis of the parameters derived from QTAIM, such as the electron density (ρ(cp)) at the H…X (X = O, N) intermolecular bond critical point (BCP) and the laplacian of the electron density (∇2(cp)) at this BCP, were found to be very useful to deepen the understanding of the nature of hydrogen bond.41 Espinosa and coworkers noted that the energy of a particular hydrogen bond (Eint) correlated with the local electron potential energy density V(rcp) (eq.2).42 With eq. 2, one could give a quantitative description of the strength of hydrogen bonds in the hydrogen bond network in transition state structures. 1

( ) = 2 ( )

Figure 6. Non-covalent interaction analysis (blue, strong attraction; green, weak interaction, and red, strong repulsion) for stereo-controlling transition states in the QD-1a catalyzed isomerization, together with their relative free energies (kcal/mol), calculated with M05-2x/6-31+G(d)(SMD).

=

≠

≠

≠

≠

∑ −∆ ( )/ −∑ −∆ ( )/ ∑ −∆ ( )/ +∑ −∆ ( )/

eq. 1

Attractive non-covalent interactions in asymmetric catalysis have been considered as the links between enzymes and small molecule catalysts.37 However, unraveling the weak interactions in transition states is nontrivial due to the subtle nature of these interactions. Recently, Yang and coworkers introduced an invaluable approach to identify non-covalent interactions on the basis of analyzing the electron densities and their reduced density gradient (RDG) isosurface.19 Such analysis is known to be able to identify the location and strength of noncovalent interactions by examining the peaks that appear in the RDG at low densities. The analysis of the electron density and the RDG for the stereo-controlling transition state structures of

eq. 2

The estimated energies (Eint) of the hydrogen bonds involved in these stereo-controlling transition state structures are summarized in Table 1. Notably, the hydrogen bonding interaction between the H10' and O1'' atoms in TS2e(s) is 1.9 kcal/mol stronger than that in TS2f(r) due to its shorter H10'…O1'' distance (1.725 in TS2e(s) vs. 1.784 in TS2f(r)). Moreover, the favorable C9-H12…O1'' and C6-H13…O3'' interactions were found to contribute 1.5 and 1.4 kcal/mol to the stability of TS2e(s), respectively. On the contrary, these two stabilizing interactions were absent in TS2f(r). It should be pointed out that there is a comparable stabilizing C5'H11'…O3'' interaction in both TS2e(s) (3.1 kcal/mol) and TS2f(r) (3.7 kcal/mol). Taking all these into account, the stabilizing C9-H12…O1'' and C6-H13…O3'' interactions and the stronger H10'…O1'' interaction cause TS2e(s) to behave differently from TS2f(r), leading to the experimentally observed selectivity. Though hydrogen bonding interaction between the H10' and O1'' atoms in TS2a(s) is only 0.4 kcal/mol weaker than that in TS2b(r), the stabilizing interaction between H11' and O3'' can contribute 3.3 kcal/mol to the stability of TS2a(s), whereas no such stabilizing interaction is present in TS2b(r). Moreover, the relatively weak C9-H12…O3'' and C5'-H11'…O1'' interactions (2.0 and 1.3 kcal/mol, respectively) in TS2a(s) as compared to those among H11'…π (C2''=C6''), H12…π (C5''=C6''), and C6-H13…O3'' (1.7, 1.3, and 1.4 kcal/mol, respectively) in TS2b(r) could also influence the stability of the former. Obviously, the presence of the medium strong C5'-H11'…O3'' interaction in TS2a(s) would be the main factor that makes it more stable than TS2b(r).



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Table 1. Estimated Strength of Hydrogen Bonds Involved in the Transition State (TS) Structures for QD-1a and QD-1b Catalyzed Isomerization (kcal/mol) TS

Type of hydrogen bonds and its energy

TS2a(s)

E(H10'…O1'')= -11.7

E(H11'…O3'')= -3.3

E(H12…O3'')= -2.0

E(H11'…O1'')= -1.3

TS2b(r)

E(H10'…O1'')= -12.1

E(H11'…π(C2''=C6''))= -1.7

E(H12…π(C5''=C6''))= -1.3

E(H13…O3'')= -1.4

TS2e(s)

E(H10'…O1'')= -12.2

E(H11'…O3'')= -3.1

E(H12…O1'')= -1.5

E(H13…O3'')= -1.4

TS2f(r)

E(H10'…O1'')= -10.3

E(H11'…O3'')= -3.7

2TS2a(s)

E(H10'…O1'')= -11.6

E(H11'…O3'')= -3.3

E(H12…O3'')= -1.7

2TS2b(r)

E(H10'…O1'')= -11.5

E(H11'…π(C2''=C6''))= -1.7

E(H12…π(C5''=C6''))= -1.3

E(H13…O3'')= -1.3

2TS2e(s)

E(H10'…O1'')= -12.2

E(H11'…O3'')= -2.7

E(H12…O1'')= -1.8

E(H13…O3'')= -0.9

2TS2f(r)

E(H10'…O1'')= -11.3

E(H11'…O3'')= -2.2

E(H12…O1'')= -1.4

--

--

---

Figure 7. Potential energy surface of QD-1b catalyzed isomerization calculated with M05-2x/6-31+G(d)(SMD).

In summary, though the conventional N-H…O or O-H…O hydrogen bonds give the most stable interactions in these transition state structures, it is the multiple weak non-conventional C-H…O hydrogen bonds that induce selectivity of the QD-1a catalyzed olefin isomerization. The B2PLYP-D/6-31+G(d,p)// M05-2x/6-31+G(d)(SMD) method predicted very similar values for these weak non-conventional C-H…O hydrogen bonds (see Table S1 in Supporting Information). From the stereo-controlling transition structure in Scenario III and I, it seems that the methyl group at C4″ of substrate would not affect the selectivity through steric interaction. To provide further verification for the proposed mechanism, the effect of the substituent at C4″ of substrate was studied by using the a-isopropyl-β,γ-butenolide as a model substrate. The calculated ee values for the QD-1a catalyzed isomerization of methyl and isopropyl substituted-β,γ-butenolide are nearly identical (see Figure S18 in Supporting Information), which is in accord with Deng and coworkers’ experimental observation. Mechanism of QD-1b Catalyzed Reaction In the early stage of asymmetric catalysis, considerable efforts were devoted to the role of steric repulsion in designing chiral catalysts.43 Recently, manipulation of electronic effect of catalyst gained increasing attention.6 Deng and coworkers’ work was just one of the successful applications of the “electronic tuning of the catalyst” strategy. By rational oxidization

of the quinoline ring N of QD-1b into its N-oxide analogue QD-1a, they achieved a significant enhancement of the catalytic activity and selectivity.5 So, it is of great interest to compare the structures and energies of the intermediates and transition states involved in the QD-1b and QD-1a catalyzed isomerizations. The information deduced from the electronic effect of catalyst on activity and selectivity would be very helpful for the design of new catalysts. The optimized transition state and intermediate structures in the QD-1b catalyzed isomerization resemble those in the QD1a catalyzed pathway (See Figures S19-S24 in Supporting Information). Similarly, the γ-protonation step is showed to be rate-limiting for QD-1b catalyzed isomerization of R1 to P1 (Figure 7). However, the different acidity of the 6'-OH group in QD-1b and QD-1a makes differences! Contrasting to the QD-1a catalyzed isomerization, the calculated overall activation free energy in Scenario I is 0.6 kcal/mol lower than that in Scenario III for the QD-1b catalyzed isomerization. This suggests that the protonated quinuclidine become a better proton donor than the 6'-OH for the catalyst QD-1b due to the decreased acidity of its 6'-OH group. In other words, QD-1b is slightly more preferred to utilize protonated quinuclidine whereas QD-1a is more preferred to 6'-OH as proton donor in the stereo-controlling step. Thus, the present calculations reveal that the catalytic mode of a given catalytic reaction may change when tuning the catalyst by varying its electronic effect.


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Moreover, when the 6'-OH group functions as proton donor in the stereo-controlling step, the overall activation free energy of the QD-1a catalyzed reaction is 2.1 kcal/mol lower than that of the QD-1b catalyzed isomerization (Scenario III in Figures 5 and 7). On the other hand, when the 6'-OH group acts a hydrogen donor in the stereo-controlling step, the overall activation free energies of the QD-1a and QD-1b catalyzed isomerization are almost the same (Scenario I in Figures 5 and 7). Thus, one can reach the conclusion that enhancing the acidity of the 6'-OH group has an obvious effect on catalytic activity when it acts as a proton donor. In addition, the QD-1b catalyzed isomerization via Scenario I requires 19.6 kcal/mol activation free energy, which is 1.5 kcal/mol greater than that of the QD-1a catalyzed same isomerization via Scenario III. (calculations using the M05-2x/6311+G(2d,p)//M05-2x/6-31+G(d)(SMD) and B2PLYP-D/631+G(d,p)//M05-2x/6-31+G(d)(SMD) methods predicted similar relative energies: see Figures S16 in Supporting Information) This explains the observed lower catalytic activity of QD-1b.

Figure 8. Non-covalent interaction analysis (blue, strong attraction; green, weak interaction, and red, strong repulsion) for stereo-controlling transition states in the QD-1b catalyzed isomerization, together with their relative free energies (kcal/mol), calculated with M05-2x/6-31+G(d) (SMD).

Origin of decreased selectivity of QD-1b catalyzed reaction Catalyst QD-1b has not only a lower catalytic activity but also a lower selectivity than those of QD-1a5 that correspond well with our calculation. The free energy difference was found by calculation to be only 0.9 kcal/mol between 2TS2a(s) and 2TS2b(r) and 0.4 kcal/mol between 2TS2e(s) and 2TS2f(r) (Figure 8), resulting in a predicted ee of 62%. Inspection of the structure of 2TS2a(s) and TS2a(s), it is clear that the H10'…O1'' distance in 2TS2a(s) is longer than that in TS2a(s) (1.712 Å vs. 1.707 Å). This suggests that R1

should bind looser with QD-1b than with QD-1a due to the low acidity of the 6'-OH group in the former. Consequently, some hydrogen bonding interactions become weakened or even vanished in 2TS2a(s) (Table 1). For example, the favorable C9-H12…O3'' interaction, which contributed 2.0 kcal/mol to the stability of TS2a(s), becomes weakened to 1.7 kcal/mol in 2TS2a(s) as a result of H12…O3'' distance lengthening from 2.522 to 2.577 Å; and the C5'-H11'…O1'' interaction, which contributed 1.3 kcal/mol to stabilizing TS2a(s), now shows a negligible effect on stability of 2TS2a(s) due to extension of the H11'…O1'' distance. On the other hand, the stabilizing C5'H11'…O3'' interaction remained unchanged due to similar bonding length in TS2a(s) and in 2TS2a(s). Besides, though the O9'-H10'…O1'' interaction is weakened from 12.1 kcal/mol in TS2b(r) to 11.5 kcal/mol in 2TS2b(r), the favorable C6H13…O3', H11'…π (C2''=C6''), and H12…π (C5''=C6'') interactions were about the same in TS2b(r) and 2TS2b(r). That is, the 2TS2a(s) favored over 2TS2b(r) altogether by only 0.9 kcal/mol. Similarly, the stabilizing C5'-H11'…O3'' and C6H13…O3'' interactions in 2TS2e(s) reduced to 2.7 and 0.88 kcal/mol as their distance increased to 2.411 Å and 2.822 Å, respectively. The stabilizing C5'-H11'…O3'' interaction reduced from 3.7 kcal/mol in TS2f(r) to 2.2 kcal/mol in 2TS2f(r) as the H11'…O3'' distance lengthened from 2.268 to 2.488 Å. Overall, the computationally predicted decrease of enantioselectivity in the QD-1b catalyzed isomerization of γ-methyl β,γ-butenolide to γ-methyl α,β-butenolide is in good agreement with experiment. The reduced enantioselectivity is originated from the looser hydrogen binding of substrate R1 with catalyst QD-1b than with QD-1a, and this causes an attenuation of the stabilizing non-conventional hydrogen interactions in the stereo-controlling transition state structures of the QD-1b catalyzed reaction. 4. Conclusion Computational study of the asymmetric olefin isomerization of β,γ- to α,β-unsaturated butenolides catalyzed by cinchona alkaloid derivatives yielded important mechanistic insights into the bio-inspired proton transfer catalysis. Firstly, the computation showed that the γ-protonation step is rate-limiting in olefin isomerization, and that both the protonated quinuclidine and 6'-OH of the catalyst may function as proton donor in the stereo-controlling step. Secondly, it was found that QD-1a prefers to utilize 6'-OH whereas QD-1b prefers slightly more to protonated quinuclidine as proton donor in the stereocontrolling step. Thus, a catalytic reaction may proceed via different pathways when the catalyst is modified simply by tuning its electronic effect. Thirdly, the non-covalent interactions in the stereo-controlling transition state were identified and their strengths were estimated quantitatively. The selectivity of the cinchona alkaloids catalyzed asymmetric olefin isomerization of β,γ- to α,β-unsaturated butenolides arises mainly from the multiple non-conventional C-H…O hydrogen bonding interactions. The experimentally observed lower stereoselectivity for this catalytic olefin isomerization with QD1b than with QD-1a was reproduced by computation, and was rationalized by the looser hydrogen binding of QD-1b with substrate as compared to the case of QD-1a, which was verified to be the primary factor leading to a reduction of the nonconventional hydrogen bonding interactions in the stereocontrolling transition state. In sum, the present calculation suggested that, for certain acid-base bifunctional chiral cata-



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lysts, the acid-base active sites of catalysts may inter-convert and yield new catalyst varieties with higher activity and selectivity. This study is thus believed to contribute to a better understanding of the so-called “Electronic tuning of asymmetric catalyst”,6d and to provide useful hints for designing the cinchona alkaloids and other acid-base bifunctional chiral catalysts promoted reactions.

ASSOCIATED CONTENT Supporting Information. Figures S1 to S31, Scheme S1 to S4, a complete citation for ref 26, experimental details and optimized geometries and energies of all computed species. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors are highly appreciative of the financial support from the National Natural Science Foundation of China (NSFC grant numbers 21172112, 51173083, and 21172118) and the National Basic Research Program of China (2010CB833300 and 2012CB821600). The reviewers’ very valuable comments and especially the suggestion of one reviewer to find experimental evidence for the computationally proposed role of QD-1a' are greatly acknowledged.

REFERENCES (1) (a) Xue, L.; Talalay, P.; Mildvan, A. S. Biochemistry. 1990, 29, 7491. (b) Austin, J. C.; Kuliopulos, A.; Mildvan, A. S.; Spiro, T. G. Protein Sci. 1992, 1, 259. (c) Hawkinson, D. C.; Pollack, R. M.; Ambulos, N. P. Biochemistry. 1994, 33, 12172. (d) Zhao, Q.; Abeygunawardana, C.; Talalay, P.; Mildvan, A. S. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 8220. (e) Zhao, Q. J.; Abeygunawardana, C.; Gittis, A. G.; Mildvan, A. S. Biochemistry. 1997, 36, 14616. (f) Massiah, M. A.; Abeygunawardana, C.; Gittis, A. G.; Mildvan, A. S. Biochemistry. 1998, 37, 14701. (2) For selected reviews, see: (a) Breslow, R. Acc. Chem. Res. 1995, 28, 146. (b) Kirby, A. J. Angew. Chem., Int. Ed.1996, 35, 706; (c) Marchetti, L.; Levine, M. ACS Catal. 2011, 1, 1090. (d) Bernardi, L.; Fochi, M.; Franchini, M. C.; Ricci, A. Org. Biomol. Chem. 2012, 10, 2911. (3) For selected reviews, see: (a) Acc. Chem. Res. 2004, 37(8), special issue on organocatalysis. (b) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005. (c) Chem Rev. 2007, 107(12), special issue on organocatalysis. (d) Dalko, P. I. Enantioselective Organocatalysis; Wiley-VCH: Weinheim, 2007. (e) Proc. Natl. Acad. Sci. U.S.A. 2010, 107(48), special feature issue on organocatalysis. (4) (a) Hintermann, L.; Schmitz, M. Adv. Synth. Catal. 2008, 350, 1469. (b) Saga, Y.; Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.2010, 132, 7905. (c) Wu, Y.; Deng, L. J. Am. Chem. Soc. 2012, 134, 14334. (d) Lee, J. H.; Deng, L. J. Am. Chem. Soc. 2012, 134, 18209. (5) Wu, Y.; Singh, R. P.; Deng, L. J. Am. Chem. Soc. 2011, 133, 12458. (6) For recent reviews, see: (a) Flanagan, S. P.; Guiry, P. J. J. Organomet. Chem. 2006, 691, 2125. (b) Xu, J. X. Curr. Org. Synth. 2010, 7, 650. For select examples (c) Hughes, D. L.; Dolling, U. H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745. (d) Jacobsen, E. N.; Zhang, W.; Guler, M. L. J. Am. Chem. Soc. 1991, 113, 6703. (e) RajanBabu, T. V.; Casalnuovo, A. L.

Page 10 of 13

J. Am. Chem. Soc. 1992, 114, 6265. (f) Nelson, D. W.; Gypser, A.; Ho, P. T.; Kolb, H. C.; Kondo, T.; Kwong, H. L.; McGrath, D. V.; Rubin, A. E.; Norrby, P. O.; Gable, K. P.; Sharpless, K. B. J. Am. Chem. Soc. 1997, 119, 1840. (g) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Guler, M. L.; Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948. (h) Yang, D.; Yip, Y.-C.; Chen, J.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120, 7659. (i) RajanBabu, T. V.; Radetich, B.; You, K. K.; Ayers, T. A.; Casalnuovo, A. L.; Calabrese, J. C. J. Org. Chem. 1999, 64, 3429. (j) Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5755. (k) Xu, J. X.; Wei, T. Z.; Zhang, Q. H. J. Org. Chem. 2004, 69, 6860 (l) Jeulin, S.; de Paule, S. D.; Ratovelomanana-Vidal, V.; Genet, J. P.; Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5799. (m) Yan, X. X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X. L.; Wu, Y. D. Angew. Chem. Int. Ed. 2006, 45, 1979. (n) Jensen, K. H.; Sigman, M. S. Angew. Chem. Int. Ed. 2007, 46, 4748. (o) Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464. (p) Yan, X.-X.; Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.L.; Wu, Y.-D. J. Am. Chem. Soc. 2008, 130, 14362. (q) Wu, H.-C.; Hamid, A. A.; Yu, J.-Q.; Spencer, J. B. J. Am. Chem. Soc. 2009, 131, 9604. (r) Korenaga, T.; Nomura, K.; Onoue, K.; Sakai, T. Chem. Commun. 2010, 46, 8624. (s) Jensen, K. H.; Sigman, M. S. J. Org. Chem. 2010, 75, 7194. (t) Harper, K. C.; Sigman, M.S. Science., 2011, 333, 1875 (u) So, S. S.; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13, 716. (v) So, S. S.; Mattson, A. E. J. Am. Chem. Soc. 2012, 134, 8798. (w)Vermoortele, F.; Vandichel, M.; Van de Voorde, B.; Ameloot, R.; Waroquier, M.; Van Speybroeck, V.; De Vos, D. E. Angew. Chem. Int. Ed. 2012, 51, 4887. (x) Xu, X.; Liu, P.; Lesser, A.; Sirois, L. E.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 11012. (7) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. (8) For selected examples, see: (a) de March, P.; Figueredo, M.; Font, J.; Raya, J.; Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 2003, 68, 2437. (b) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993. (c) Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410. (9) For selected recent examples, see: (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. (b) Braukmüller, S.; Brüuckner, R. Eur. J. Org. Chem. 2006, 2110. (c) Kapferer, T.; Brückner, R. Eur. J. Org. Chem. 2006, 2119. (d) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 15572. (e) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2319. (f) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131,4572. (g) Zhang, Y.; Yu, C.; Ji, Y.; Wang, W. Chem.; Asian J. 2010, 5,1303. (h) Wang, J.; Qi, C.; Ge, Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 46, 2124. (i) Ube, H.; Shimada, N.; Terada, M. Angew. Chem. Int. Ed. 2010, 49, 1858. (j) Cui, H.; Huang, J.; Lei, J.; Wang, Z.; Chen, S.; Wu, L.; Chen, Y. Org. Lett. 2010, 12, 720. (k)Yang, Y.; Zheng, K.; Zhao, J. N.; Shi, J. A.; Lin, L. L.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2010, 75, 5382. (l) Zhou, L.; Lin, L. L.; Ji, J.; Xie, M. S.; Liu, X. H.; Feng, X. M. Org. Lett. 2011, 13, 3056. (m) Pansare, S. V.; Paul, E. K. Chem. Commun. 2011, 47, 1027. (n) Mao, B.; Geurts, K.; FañanásMastral, M.; van Zijl, A. W.; Fletcher, S. P.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2011, 13, 948. (10) For representative examples, see: (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911. (c) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106, 5155. (d) Clemente, F. R.; Houk, K. N. Angew. Chem., Int. Ed.2004, 43, 5766. For reviews: (e) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H. Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558. (f) Sunoj, R. B. WIREs Comput. Mol. Sci. 2011, 1, 920. and references cited therein. (11) For selected examples, see: (a) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217. (b) Dudding, T.; Houk, K. N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5770. (c) Xu, S. J.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem.-Eur. J. 2005, 11, 4751. (d) Singleton, D. A.; Wang, Z. H. J. Am. Chem. Soc. 2005, 127, 6679. (e) Gordillo, R.; Houk, K. N. J. Am. Chem. Soc. 2006, 128, 3543. (f) Zhang, X.; Du, H.; Wang, Z.; Wu, Y.-D.; Ding, K. J. Org. Chem. 2006, 71, 2862. (g) Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. J. Am.


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Chem. Soc. 2006, 128, 13151. (h) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756. (i) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (j) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J. Org. Chem. 2007, 72, 4001. (k) Fu, A. P.; Li, H. L.; Yuan, S. P.; Si, H. G.; Duan, Y. B. J. Org. Chem. 2008, 73, 5264. (l) Li, X.; Ye, S.; He, C.; Yu, Z-Y. Eur. J. Org. Chem. 2008, 25, 4296. (m) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358. (n) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001. (o) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062. (p) Lu, T. X.; Zhu, R. X.; An, Y.; Wheeler, S. E. J. Am. Chem. Soc. 2012, 134, 3095. (q) Lam, Y. -h.; Houk, K. N.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2012, 134, 6286. (12) (a) Houk, K. N.; Cheong, P. H. Y. Nature. 2008, 455, 309. (b) Cheong, P. H. Y.; Legault, C. Y.; Um, J. M.; Celebi-Ölcüm, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042. (13) For preliminary reports: (a) Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron. Lett. 1977, 2181. (b) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417. For recent reviews, see: (c) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961. (d) Tian, S. K.; Chen, Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (e) Chen, Y.C. Synlett. 2008, 13, 1919. (f) Bartoli, G.; Melchiorre, P. Synlett. 2008, 12, 1759. (g) Song, C. E. Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis, Song C. E., Ed, Wiley-VCH, Weinheim, 2009. (h) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229. (i) Jiang, L.; Chen, Y. C. Catal. Sci. Technol.2011, 1, 354. (j) Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron. 2011, 67, 1725. (k) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 2. (14) For examples of 6'-OH cinchona alkaloids, see: (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. (b) Li, H. M.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (c) Li, H. M.; Song, J.; Liu, X. F.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948. (d) Li, H. M.; Wang, Y.; Tang, L.; Wu, F. H.; Liu, X. F.; Guo, C. Y.; Foxman, B. M.; Deng, L. Angew. Chem.,Int. Ed. 2005, 44, 105. (e) Li, H. M.; Wang, B. M.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (f) Wu, F. H.; Hong, R.; Khan, J. H.; Liu, X. F.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301. (g) Wang, Y.; Liu, X. F.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (h) Wang, B. M.; Wu, F. H.; Wang, Y.; Liu, X. F.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (i) Wang, Y.; Li, H. M.; Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364. (j) van Steenis, D. J. V. C.; Marcelli, T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. Adv. Synth. Catal. 2007, 349, 281. (k) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L. Chem. Sci. 2011, 2, 1301. (l) Bartelson, K. J.; Singh, R. P.; Foxman, B. M.; Deng, L. Chem. Sci. 2011, 2, 1940. (m) Xiao, X.; Xie, Y.; Su, C.; Liu, M.; Shi, Y. J. Am. Chem. Soc. 2011, 133, 12914. (15) For examples of C-9 substituted (thio)urea-, sulfonamide-, and squaramide derivatives, see: (a) Li, B. J.; Jiang, L.; Liu, M.; Chen, Y. C.; Ding, L. S.; Wu, Y. Synlett 2005, 603. (b) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967. (c) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (d) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (e) Wang, Y. Q.; Song, J.; Hong, R.; Li, H. M.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156. (f) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418. (g) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (h) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (i) Diner, P.; Nielsen, M.; Bertelsen, S.; Niess, B.; Jorgensen, K. A. Chem. Commun. 2007, 3646. (j) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed. 2008, 47, 7872. (k) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. (l) Connon, S. J. Synlett 2009, 354. (m) Liu, Y.; Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418. (n) Lee, J. W.; Ryu, T. H.; Oh, J. S.; Bae, H. Y.; Bin Jang, H.; Song, C. E. Chem. Commun. 2009, 7224. (o) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028. (p) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153. (q) Park, S. E.; Nam, E. H.; Bin Jang, H.; Oh,

J. S.; Some, S.; Lee, Y. S.; Song, C. E. Adv. Synth. Catal. 2010, 352, 2211. (r) Peschiulli, A.; Procuranti, B.; O' Connor, C. J.; Connon, S. J. Nat. Chem. 2010, 2, 380. (s) Gleeson, O.; Davies, G.-L.; Peschiulli, A.; Tekoriute, R.; Gun'ko, Y. K.; Connon, S. J. Org. Biomol. Chem. 2011, 9, 7929. (t) Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2011, 133, 16711. (u) Cornaggia, C.; Manoni, F.; Torrente, E.; Tallon, S.; Connon, S. J. Org. Lett. 2012, 14, 1850. (v) Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.; Battistini, L.; Zanardi, F.; Casiraghi, G. Angew. Chem. Int. Ed. 2012, 51, 6200. (w) Albertshofer, K.; Tan, B.; Barbas III, C. F. Org. Lett. 2012, 14, 1834. (16) For examples of cinchona alkaloid primary amine derivatives, see: (a) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2007, 46, 7667. (b) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413. (c) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (d) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389. (e) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599. (f) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2008, 47, 7656. (g) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am. Chem. Soc. 2008, 130, 2422. (h) Lu, X. J.; Deng, L. Angew. Chem. Int. Ed. 2008, 47, 7710. (i) Gogoi, S.; Zhao, C.-G.; Ding, D. Org. Lett. 2009, 11, 2249. (j) Lu, X. J.; Liu, Y.; Sun, B. F.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134. (k) Wu, L.-Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7196. (l) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (m) Paixao, M. W.; Holub, N.; Vila, C.; Nielsen, M.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2009, 48, 7338. (n) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.M.; Song, Y.-L. J. Am. Chem. Soc. 2009, 131, 14626. (o) Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132, 10227. (p) Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20642. (q) Holub, N.; Jiang, H.; Paixao, M. W.; Tiberi, C.; Jorgensen, K. A. Chem.;Eur. J. 2010, 16, 4337. (r) Qiao, Z.; Shafiq, Z.; Liu, L.; Yu, Z.-B.; Zheng, Q.Y.; Wang, D.; Chen, Y.-J. Angew. Chem., Int. Ed. 2010, 49, 7294. (s) Tan, B.; Candeias, N. R.; Barbas III, C. F. Nat. Chem. 2011, 3, 473. (t) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 1738. (u) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 17934. (v) Cai, Q.; You, S.-L. Org. Lett. 2012, 14, 3040. (17) (a)Vayner, G.; Houk, K. N.; Sun, Y. K. J. Am. Chem. Soc. 2004, 126, 199. (b) Hammar, P.; Marcelli, T.; Hiemstra, H.; Himo, F. Adv. Synth. Catal. 2007, 349, 2537. (c) Celebi-Ölcüm, N.; Aviyente, V.; Houk, K. N. J. Org. Chem. 2009, 74, 6944. (d) Cucinotta, C. S.; Kosa, M.; Melchiorre, P.; Cavalli, A.; Gervasio, F. L. Chem.-Eur. J. 2009, 15, 7913. (e) Cook, T. C.; Andrus, M. B.; Ess, D. H. Org. Lett. 2012, 14, 5836. (f) Sengupta, A.; Sunoj, R. B. J. Org. Chem. 2012, 77, 10525. (g) Zhu, J.-L.; Zhang, Y.; Liu, C.; Zheng, A.-M.; Wang, W. J. Org. Chem. 2012, 77, 9813. For a review: (h) Marcelli, T. WIREs Comput. Mol. Sci. 2011, 1, 142. (18) (a) Li, X.; Deng, H.; Zhang, B.; Li, J. Y.; Zhang, L.; Luo, S. Z.; Cheng, J. -P. Chem. Eur. J. 2010, 16, 450. (b) Xue, X. S.; Yu, A.; Cai, Y.; Cheng, J. -P. Org. Lett. 2011, 13, 6054. (c) Li, X.; Xue, X. S.; Liu, C.; Wang, B.; Tan, B. X.; Jin, J. L.; Zhang, Y.-Y.; Dong, N.; Cheng, J. -P. Org. Biomol. Chem. 2012, 10, 413. (d) Li, X.; Zhang, Y.-Y.; Xue, X.S.; Jin, J.-L.; Tan, B.-X.; Liu, C.; Dong, N.; Cheng, J.-P. Eur. J. Org. Chem. 2012, 1774. (19) (a) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; ContrerasGarcia, J.; Cohen, A. J.; Yang, W. T. J. Am. Chem. Soc 2010, 132, 6498. (b) Contreras-Garcia, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J. P.; Beratan, D. N.; Yang, W. T. J. Chem. Theory Comput. 2011, 7, 625. (20) For a recent review on weak hydrogen bonds: Takahashi, O.; Kohno, Y.; Nishio, M. Chem. Rev. 2010, 110, 6049. (21) For examples (a) Washington, Y.; Houk, K. N. Angew. Chem., Int. Ed. 2001, 40, 4485. (b) Cannizzaro, C. E.; Houk, K. N. J. Am. Chem. Soc. 2002, 124, 7163. (c) Bahmanyar, S.; Houk, K. N.; Martin,



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475. (d) Krenske, E. H.; Houk, K. N. Acc. Chem. Res.2012, DOI:10.1021/ar3000794. and references cited herein. (22) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (b) Yu, X.; Wang, W. Chem. Asian. J. 2008, 3, 516. (c) Connon, S. J. Chem. Commun. 2008, 2499. (d) Wang, Y.; Deng, L. In Catalytic Asymmetric Synthesis; ed I. Ojima, 2010, pp 59–94. (e) Quigley, C.; Rodríguez Docampo, Z.; Connon, S. J. Chem. Commun. 2012, 48, 1443. (23) (a) Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Phys. 2005, 123, 161103. (b) Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory Comput. 2006, 2, 364. (c) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2006, 2, 1009. (d) Zhao, Y.; Truhlar, D. G. Theo. Chem. Acc. 2008, 120, 215. (e) Zhao, Y.; Truhlar, D. G. Chem. Acc. Res. 2008, 41 157. (f) Zhao, Y.; Truhlar, D. G. Chem. Phys. Lett. 2011, 502, 1. (24) (a) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B. 2009, 113, 6378. (b) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B. 2011, 115, 14556. (25) (a) Schwabe, T.; Grimme, S. Phys. Chem. Chem. Phys. 2007, 9, 3397. (b) Schwabe, T.; Grimme, S. Acc. Chem. Res. 2008, 41, 569. (26) Frisch, M. J.; et al. Gaussian 09, Revision B.01: Gaussian, Inc.: Wallingford, CT, (2009). (27) (a) CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009. (http://www.cylview.org). (b) Humphrey, W.; Dalke, A.; Schulten, K. J. Mol. Graphics.. 1996,14, 33. (28) A comprehensive conformational study for catalyst and transition states was performed (as referee suggested). The detailed description and the relevant data were summarized in Supporting Information (see Part A) for the clarity and concision of the manuscript. (29) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407. (30) Gomez-Bengoa, E.; Linden, A.; López, R.; Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008, 130, 7955. (31) The unexpectedly high dissociation energy of CP2a is found to have no experimental or theoretical precedent in literature. It is only the finding of this computation by using three different methods which led to the same conclusion. (32) Meot-Ner, M. Chem. Rev. 2005, 105, 213. (33) (a) Mason, S. F. J. Chem. Soc. 1957, 5010. (b) Mason, S. F.; Philip, J.; Smith, B. E. J. Chem. Soc. A 1968, 3051. (c) Poizat, O.; Bardez, E.; Buntinx, G.; Alain, V. J. Phys. Chem. A 2004, 108, 1873. (34) Solntsev, K. M.; Clower, C. E.; Tolbert, L. M.; Huppert, D. J. Am. Chem. Soc. 2005, 127, 8534. (35) It should be pointed out that other tautomeric form of QD-1a might also exist, but QD-1a' should be the most important one. (See Scheme S4 for other possible tautomers of QD-1a). (36) An additional transition state structure TS2ee' corresponding to proton H7'' moving from C6'' (CP2e) to C4'' (CP2e’) in Scenario III was located (Figure S14 in Supporting Information) according to one reviewer’s suggestion. However, the TS2ee' was found to be only 1.8 kcal/mol higher than CP2e, indicating that this process would be very facile. For the comparison of the three mechanistic pathways, it was given in Figure S14 instead of in Figures 4 and 5. Please see Supporting Information for details. (37) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20678. (38) Lu, T.; Chen, F. W. J. Comput. Chem. 2012, 33, 580. (39) For selected examples (a) Krenske, E. H.; Houk, K. N.; Harmata, M. Org. Lett. 2010, 12, 444. (b) Antoline, J. E.; Krenske, E. H.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2011, 133, 14443. (40) (a) Bader, R. F. W. Acc. Chem. Res. 1985, 18, 9. (b) Bader, R. F. W. Chem. Rev. 1991, 91, 893. (c) Quantum Theory of Atoms in Molecules: Recent Progress in Theory and Application; Matta, C., Boyd, R. J., Eds.; Wiley-VCH: New York, 2007 (41) Grabowski, S. J. Chem. Rev. 2011, 111, 2597. and references cited herein. (42) Espinosa, E.; Molins, E.; Lecomte, C. Chem. Phys. Lett. 1998, 285, 170.

Page 12 of 13

(43) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis, John Wiley; New York, 1994. (b) Ojima, I. Catalytic Asymmetric Synthesis 2nd ed., John Wiley: New York, 2004.


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